The aim of the proposed work is to elucidate the function of pancreatic somatostatin under normal conditions and in diabetes mellitus. Although the main emphasis will be on pancreatic somatostatin, studies of gut somatostatin and of somatostatin in other sites will be carried out concurrently because of the demonstration of a widespread disorder of somatostatin cells in diabetes. The secretion of somatostatin from the normal pancreas and from the normal and diabetic stomach will be studied using as models monolayer cultures of neonatal rat pancreas and isolated perfused rat stomach. The full extent of the tissue abnormality of somatostatin in diabetes will be determined in animal models especially streptozotocin diabetic rats, spontaneously diabetic Wistar rats and obob mice. The tissue changes will be correlated with measurements of somatostatin in extracted portal and peripheral plasma. Circulating somatostatin levels will also be determined in insulin dependent and non-insulin dependent diabetic patients and interpreted in the light of the findings in the animal models. In view of the heterogeneity of tissue and circulating forms of somatostatin, the two high molecular weight forms of immunoreactivity previously described will be fully characterized, their relative distribution in tissues and plasma in normal and diabetic states determined, and thier relationship to tetradecapeptide somatostatin as precursors elucidated with the aid of biosynthesis experiments.